Prostate cancer (PCa) incidence and mortality rate is higher in African American (AA) men than in Caucasian Americans (CAs). AA men with PCa also present with higher tumor volume, more advanced tumor stage, and higher Gleason grade. Prostate carcinogenesis and tumor progression are related strongly to the expression and activity of the androgen receptor (AR). Mutations and genomic amplification of AR also can increase AR expression and/or activity. In CAs, AR mutations are infrequent (<1%) in localized tumors, but occur at a higher frequency in advanced, metastatic, or hormone-refractory disease. In AAs, the prevalence of AR mutations and their prognostic significances in primary PCa are unknown. We discovered genomic amplification and somatic mutation of AR in a PCa cell line established by our laboratory from an AA patient with localized PCa. We analyzed a set of 91 radical prostatectomy samples (57 AAs and 34 CAs) in which we identified 8 AR mutations (7 somatic and 1 germline) in AA patients, but found no mutations in CA patients. These data led us to hypothesize that AR mutations in primary African Americans PCa is more frequent than expected and may contribute to disease aggressiveness or serve as a prognostic factor. Our Specific Aims are: Aim 1: Determine the prevalence of AR mutations in primary African Americans PCa. Exon-specific primers of the AR gene will be used to sequence genomic-DNA extracted from laser-captured cells of paraffin- embedded tissue sections of radical prostatectomy specimens in order to determine the prevalence of somatic AR mutations in 400 AA patients with primary untreated PCa, and compare this frequency of mutation with that observed in 100 equivalent CA patients. Aim 2: Determine the contribution of AR mutation to PCa heterogeneity in African Americans. Clinical and histopathological heterogeneity of PCa present a major challenge to therapeutic interventions. Differences in AR expression and microvascular density are considered as the two major contributors to PCa heterogeneity. We will use flow cytometry and immunohistochemical staining to examine AR and microvessel density in AA PCa with mutated AR. Aim 3: Define the prognostic significance of AR mutations in primary African American PCa. We will determine the prognostic significance of AR mutations alone or in combination with AR density or microvessel density in relation to clinical or histopathological variables including age, PSA, Gleason score, pathological stage, biochemical recurrence, and family history, with a focus on Gleason sum or pattern as a central prognostic marker. Significance: The results of this exploratory project will provide new knowledge about both the prevalence and prognostic value of AR mutations and may help us to understand better and address more effectively the potential racial disparity between PCa aggressiveness in AAs and CAs. PUBLIC HEALTH RELEVANCE: The incidences, mortality, and aggressiveness of prostate cancer (PCa) in African-American (AA) men are higher than in Caucasians. To understand and address the racial disparity of the disease aggressiveness, reliable prognostic factors are needed. Our discovery of a high frequency of androgen receptor mutations in untreated localized AA PCa might have prognostic significance that would provide us a more effective therapeutic approach.